Abstract 2160: Quantitative proteomics of antibody-drug conjugates and chemotherapy targets in prostate cancer
Authors: Sheeno P. Thyparambil, Wei-Li Liao, Robert Heaton, Amanda Strasbaugh, Marya Melkie, Negin Ghafourian, Xuefeng B. Ling
Journal: Cancer Research (2023)

Abstract Introduction: Prostate cancer therapy involves the use of androgen deprivation therapy, chemotherapy, targeted therapy and immunotherapy. Chemotherapy involves the use of anti-tubulins (docetaxel, cabazitaxel), platinum salts, and topoisomerase inhibitors (TOPO1, TOPO2A). There is no biomarker of chemotherapy that is routinely used. We examined 87 prostate cancer samples using targeted proteomics for biomarkers of response or resistance to chemotherapy agents. Biomarkers of resistance include ERCC1 (Platinum), TUBB3 (taxanes), ALDH1A1 (cyclophosphamide), while response biomarkers include TOPO1 (irinotecan, topotecan), TOPO2A (doxorubicin, epirubicin), and hENT1 (Gemcitabine). We also measured markers for several antibody-drug conjugates targets (Her2, Her3, Trop2) in our clinical proteomics (CLIA) platform and several ADC/CAR-T proteins (PSMA, STEAP1, Nectin4, Claudin 18.2. in our research platform Methods: Tumor areas from Formalin-fixed, paraffin-embedded (FFPE) tumor tissues from clinical samples of prostate cancer received at our CLIA certified laboratory were microdissected and a quantitative proteomic analysis of 72 biomarkers were conducted using selected reaction monitoring mass spectrometry (SRM-MS). Discussion:[WL1] Androgen receptor was detected in majority of the samples (83%) with a 19x range of distribution (329 amol/ug - 24063 amol/µg). Majority of prostate cancer samples expressed a range of resistance markers for anti-tubulin inhibitors (TUBB3: 69% detection with a 14x range) indicating that the high expressors is likely to be resistant to docetaxel/cabazitaxel based regimens. ERCC1, a marker for resistance to platinum-based agents, was not detected in 26% of cases, potentially enabling a cisplatin/carboplatin-based regimen in 1/4th of prostate cancer patients. Cyclophosphamide could be effective in 10% of cases where ALDH1A1 was not detected. TOPO1, a marker for irinotecan-based therapy was observed in 94% of cases with a range of ~6x (488 - 2760 amol/µg). Other chemotherapy agents that are not routinely used in prostate cancer was observed in select groups. These include doxorubicin biomarker TOPO2A in 34% of cases with 10x range, gemcitabine biomarker hENT1 in 36% of cases (4x range), temozolomide biomarker MGMT (ND in 12% of cases). ADC biomarker analysis revealed HER2 which was observed in 59% of the cases with range of expression from 301 - 1255 amol/µg including a significant population of low HER2 (84%, &amp;lt;750 amol/µg) cases among the detected samples. HER3 was detected in 33% of cases with a 3x range (178 - 580 amol/µg). EGFR was detected in 94% of samples at levels ranging from 131-1125 amol/µg. Trop2 was quantitated in 93% of the cases and had wide range of 37x (437 -16267 amol/µg). The capacity to multiplex 72 protein biomarkers from 2-3 FFPE sections yields a wealth of actionable information for clinical treatment or patient stratification in clinical trials. Citation Format: Sheeno P. Thyparambil, Wei-Li Liao, Robert Heaton, Amanda Strasbaugh, Marya Melkie, Negin Ghafourian, Xuefeng B. Ling. Quantitative proteomics of antibody-drug conjugates and chemotherapy targets in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2160.